45 STOMACH PHYSIOLOGY & GASTRIC ACID REGULATION

# Detailed notes

The stomach is a muscular reservoir that mechanically churns food, sterilises it with acid, begins protein digestion and meters chyme into the duodenum. Understanding it for MRCS Part A means understanding three things together: which cell secretes what, how acid secretion is switched on and off, and what happens when this machinery is deranged by disease or surgery.

Gross anatomy in one paragraph

The stomach has five regions — cardia (around the oesophagogastric junction), fundus (dome above the cardia, often gas-filled on AXR), body (the main acid-secreting region), antrum (distal third, where G cells live) and pylorus (sphincter into the duodenum). The lesser curvature runs along the right border (supplied by the left and right gastric arteries) and the greater curvature along the left (supplied by right and left gastroepiploic arteries, plus short gastrics from the splenic artery). All five vessels are branches of the coeliac trunk directly or indirectly — a favourite exam fact.

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Cell types — know these cold

The mucosa contains five secretory cell types. Every MRCS Part A candidate must be able to match cell to product and product to function.

Cell	Location	Secretes	Function
Parietal (oxyntic)	Body & fundus	HCl, intrinsic factor	Acid digestion; IF binds B12 for terminal ileal absorption
Chief	Body & fundus	Pepsinogen	Cleaved by acid to pepsin (protein digestion)
G cells	Antrum	Gastrin	Stimulates parietal cells, trophic to mucosa
D cells	Antrum & body	Somatostatin	Master inhibitor of acid and gastrin
ECL (enterochromaffin-like)	Body	Histamine	Paracrine drive of parietal cells
Mucous neck cells	Throughout	Mucus + HCO3−	Surface protection

👩‍⚕️ The single most testable mismatch: gastrin comes from the antrum, not the body. The body is where the acid is made; the antrum is where the signal to make it comes from.

Wall layers

Standard four layers (mucosa, submucosa, muscularis externa, serosa), but with a unique trick: the muscularis externa has three layers instead of two — inner oblique, middle circular, outer longitudinal. The extra oblique layer allows the vigorous churning needed to liquefy a meal.

[Image: Schematic of the five gastric cell types within a gastric gland, with their products labelled]

Gastric acid regulation — the three phases

Acid secretion is described in three sequential phases. Examiners love this framework.

1. Cephalic phase (~30%) — sight, smell, taste and thought of food. Mediated by the vagus nerve (ACh on parietal M3 receptors, ACh on G cells via GRP).

2. Gastric phase (~60%) — gastric distension (vago-vagal reflex) and peptides/amino acids in the lumen stimulating G cells to release gastrin.

3. Intestinal phase (~10%) — initially mildly stimulatory (amino acids in duodenum), then becomes inhibitory as acid, fat and hyperosmolar chyme trigger secretin, CCK and GIP from the duodenum.

The three direct stimulators of the parietal cell

Three molecules converge on the parietal cell. Block any one and you reduce acid; block their common downstream pump and you abolish it.

- Acetylcholine (from the vagus) → M3 receptor → Gq → IP3/DAG → ↑Ca²⁺

- Gastrin (from G cells) → CCKB receptor → Gq → IP3/DAG → ↑Ca²⁺ (also acts on ECL cells)

- Histamine (from ECL cells) → H2 receptor → Gs → ↑cAMP → PKA

All three pathways activate the H⁺/K⁺ ATPase (proton pump) on the apical canalicular membrane. This is the final common pathway — the target of PPIs.

👩‍⚕️ Histamine is the most direct and most potent stimulator because every parietal cell sits next to an ECL cell, and gastrin and ACh both also act through ECL cells (amplification). That's why H2 blockers and PPIs are effective even when you can't block vagus or gastrin.

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The inhibitors

The brake system is just as examinable as the accelerator.

- Somatostatin (D cells) — the master switch. Inhibits gastrin release (paracrine on G cells) and parietal cells directly (SSTR2, Gi, ↓cAMP). Triggered by low luminal pH — a negative feedback loop.

- Secretin (duodenal S cells, in response to acid and fat) — inhibits gastrin, stimulates pancreatic bicarbonate from ductal cells, stimulates biliary bicarbonate.

- CCK (duodenal I cells, in response to fat and amino acids) — stimulates pancreatic enzyme secretion from acinar cells, contracts gallbladder, relaxes sphincter of Oddi, delays gastric emptying.

- GIP (K cells) — inhibits acid, stimulates insulin (the original incretin).

- Prostaglandins (PGE2, PGI2) — inhibit acid via EP3 (↓cAMP) and stimulate protective mucus/bicarbonate. NSAIDs remove this protection, hence NSAID-induced ulcers.

👩‍⚕️ A clean way to remember secretin vs CCK: Secretin = Solution (bicarbonate, watery juice). CCK = Catalysts (enzymes) and Contraction (gallbladder).

Acid-suppression drugs

- Proton pump inhibitors (omeprazole, lansoprazole) — irreversibly bind the activated H⁺/K⁺ ATPase. Effect persists until new pumps are synthesised, so the clinical effect outlasts the short plasma half-life.

- H2 receptor antagonists (ranitidine, cimetidine) — competitive H2 block. Cimetidine inhibits cytochrome P450 (warfarin, phenytoin, theophylline interactions) and causes gynaecomastia from anti-androgen effects.

- Antacids — neutralise acid in the lumen; no effect on secretion.

Pathology you must recognise

Zollinger-Ellison syndrome

A gastrinoma — most often in the "gastrinoma triangle" (junction of cystic and common bile duct, junction of 2nd/3rd part of duodenum, junction of neck/body of pancreas). 25% are part of MEN1 (parathyroid, pancreas, pituitary). Classic features:

- Multiple peptic ulcers, often in atypical sites (distal duodenum, jejunum)

- PPI-resistant ulceration

- Secretory diarrhoea (acid inactivates pancreatic enzymes → steatorrhoea)

- Markedly raised fasting gastrin + paradoxical rise on secretin stimulation test (normally secretin suppresses gastrin)

Autoimmune atrophic gastritis / pernicious anaemia

Autoantibodies against parietal cells and intrinsic factor → loss of acid and IF → B12 malabsorption → megaloblastic macrocytic anaemia. Achlorhydria triggers compensatory hypergastrinaemia (no acid to switch off G cells), leading to ECL hyperplasia and a long-term risk of gastric adenocarcinoma and carcinoid tumours.

Ménétrière disease

Rare hypertrophic gastropathy. Giant rugal folds, excess mucus, protein-losing gastropathy (hypoalbuminaemia, oedema), decreased acid secretion, and increased long-term risk of gastric adenocarcinoma.

Post-gastrectomy syndromes

- Dumping syndrome — loss of pyloric reservoir function.

- Early (15–30 min): hyperosmolar chyme floods the small bowel → fluid shift → cramps, diarrhoea, hypotension, tachycardia.

- Late (1–3 h): rapid glucose absorption → exaggerated insulin release → reactive hypoglycaemia (sweating, tremor, palpitations, confusion).

- Bile reflux gastritis — duodenogastric reflux of bile damages mucosa; burning epigastric pain unrelieved by antacids.

- Delayed gastric emptying — vagotomy (often performed alongside gastrectomy) abolishes receptive relaxation and peristaltic coordination.

- B12 deficiency — loss of parietal cells / IF.

Gastric adenocarcinoma

Risk factors: H. pylori, smoked/salted food, pernicious anaemia, atrophic gastritis, blood group A, smoking. Histology: signet ring cells (diffuse type) infiltrating diffusely produce linitis plastica — the rigid "leather bottle" stomach. Metastatic signatures examined in MRCS:

- Virchow's node — left supraclavicular lymph node (Troisier's sign)

- Krukenberg tumour — bilateral ovarian metastases of signet ring cells

- Sister Mary Joseph nodule — umbilical metastasis

- Blumer's shelf — palpable mass on PR (pouch of Douglas deposit)

Posterior vs anterior gastric perforation

- Anterior perforation → contents into greater sac → generalised peritonitis, free gas under diaphragm.

- Posterior perforation → contents into the lesser sac (omental bursa) first, since the lesser sac lies directly behind the stomach. May later track into the greater sac via the foramen of Winslow.

[Image: MCQs banner]

# Test yourself

Which is true of gastrin?

• ((Gastrin increases gastric acid secretion::True but not the most distinguishing feature — every stimulator does this.))
• ((Gastrin is secreted from the gastric body::G cells live in the antrum, not the body.))
• ((Gastrin increases pancreatic bicarbonate::That is secretin, from duodenal S cells.))
• ((PPIs inhibit gastrin production::PPIs raise pH and therefore increase gastrin via loss of D-cell brake.))
• ((Gastrin has a trophic effect on gastric mucosa::☑️ Drives hyperplasia of body/fundic mucosa — explains ECL hyperplasia in ZES and on long-term PPIs.))

Which cells does gastrin act on to increase acid secretion?

• ((Parietal cells::☑️ Gastrin binds CCKB receptors on parietal cells → IP3/DAG/Ca²⁺ → HCl.))
• ((Chief cells::Secrete pepsinogen; stimulated by acid, not directly by gastrin.))
• ((G cells::G cells produce gastrin; they don't respond to it.))
• ((D cells::D cells release somatostatin — they inhibit acid.))
• ((Mucous neck cells::Secrete protective mucus, not acid.))

👩‍⚕️ Gastrin also acts on ECL cells (CCKB) → histamine → H2 on parietal cells. Dual hit.

Stimulation of which cell directly increases gastric acid?

• ((Chief cells::Pepsinogen, not acid.))
• ((Brunner's glands::Duodenal alkaline mucus — opposite role.))
• ((Parietal cells::☑️ The only acid-secreting cell; activated by ACh, gastrin and histamine.))
• ((CCK release::CCK targets pancreas and gallbladder, not parietal cells.))
• ((D cells::Release somatostatin — inhibits acid.))

Which stimulates gastrin release?

• ((Adrenaline::Sympathetic activity inhibits GI secretion.))
• ((Glucagon::Inhibits gastric acid.))
• ((Calcitonin::No significant gastric role.))
• ((Acetylcholine::☑️ Vagal ACh acts on G cells (via GRP/muscarinic) — cephalic phase.))
• ((Somatostatin::The principal inhibitor of G cells.))

👩‍⚕️ Stimulators of gastrin: distension, amino acids (phenylalanine, tryptophan), vagal ACh/GRP. Inhibitor: low luminal pH (via somatostatin) — a clean negative feedback loop.

Gastric acid secretion depends on which three stimulators?

• ((Gastrin, vagal ACh, histamine::☑️ The three converging inputs on the parietal cell.))
• ((Gastrin, vagal, secretin::Secretin inhibits acid.))
• ((Gastrin, CCK, secretin::CCK and secretin both inhibit acid.))
• ((Histamine, serotonin, gastrin::Serotonin is not a major acid stimulator.))
• ((ACh, secretin, histamine::Secretin inhibits acid.))

Which intracellular messenger decreases acid secretion?

• ((Calcium::Mediates gastrin and ACh — stimulatory.))
• ((IP3/DAG::Raise calcium — stimulatory.))
• ((Decreased cAMP::☑️ Somatostatin, PGE2 and noradrenaline act via Gi to lower cAMP and shut down the pump.))
• ((cGMP::Not a major parietal-cell second messenger.))
• ((Protein kinase C::Downstream of DAG — stimulatory.))

Which inhibits gastric acid secretion?

• ((Gastrin::Stimulator via CCKB.))
• ((PGE2::☑️ Binds EP3 (Gi), lowers cAMP, reduces acid; NSAIDs remove this protection.))
• ((NSAIDs::Remove prostaglandin protection — increase acid-related damage.))
• ((Vagal stimulation::Stimulatory via ACh/M3.))
• ((Histamine::Stimulatory via H2.))

👩‍⚕️ Direct parietal-cell inhibitors: somatostatin (master), PGE2/PGI2, noradrenaline (α2), secretin, GIP, VIP.

Recurrent PUD despite PPIs and H. pylori eradication — what's raised?

• ((CCK::Doesn't cause PUD.))
• ((Histamine::Wouldn't be PPI-resistant — PPIs block its final pathway.))
• ((Secretin::Inhibits acid.))
• ((Gastrin::☑️ Zollinger-Ellison syndrome — gastrinoma in the gastrinoma triangle, often MEN1.))
• ((Somatostatin::Protective if raised.))

👩‍⚕️ Diagnosis: fasting gastrin + secretin stimulation test (gastrin paradoxically rises).

Which hormone increases pancreatic bicarbonate secretion?

• ((Secretin::☑️ Duodenal S cells respond to acid chyme; act on pancreatic ductal cells.))
• ((CCK::Stimulates enzyme-rich juice from acinar cells.))
• ((Histamine::No pancreatic role.))
• ((Serotonin::No major role here.))
• ((Gastrin::Targets parietal cells.))

👩‍⚕️ Secretin = Solution (HCO3−). CCK = Catalysts + Contraction (enzymes + gallbladder).

Atrophic gastritis with anaemia — what's the blood film?

• ((Macrocytic::☑️ Loss of parietal cells → loss of intrinsic factor → B12 malabsorption → megaloblastic macrocytosis.))
• ((Microcytic::Iron deficiency, thalassaemia — different pathway.))
• ((Spherocytes::Hereditary spherocytosis / AIHA.))
• ((Normocytic::Possible in chronic disease, but B12 typically macrocytic.))
• ((Target cells::Thalassaemia, liver disease, post-splenectomy.))

Pernicious anaemia — antibodies against what?

• ((Parietal cells::☑️ Antibodies against parietal cells and intrinsic factor cause B12 deficiency.))
• ((Chief cells::Not a recognised autoimmune target here.))
• ((Thyroid::May coexist (autoimmune polyendocrine) but isn't the cause.))
• ((Antiphospholipid::Causes APS, not pernicious anaemia.))
• ((Anticardiolipin::Same — APS.))

Pernicious anaemia patient on IM B12 develops haematemesis, weight loss and microcytic anaemia. Diagnosis?

• ((Atrophic gastritis::Already present — causes macrocytosis, not bleeding.))
• ((Gastric cancer::☑️ Atrophic gastritis is a premalignant condition; iron-deficiency microcytosis suggests chronic GI blood loss.))
• ((Duodenal ulcer::Doesn't usually cause weight loss.))
• ((Oesophageal varices::No portal hypertension cue.))
• ((Coeliac disease::Malabsorption, but not haematemesis.))

Ménétrière disease — most likely finding?

• ((Hyperacidity::Ménétrière causes hypoacidity.))
• ((Hypoalbuminaemia::☑️ Protein-losing gastropathy through hypertrophic mucosa.))
• ((B12 deficiency::Not the hallmark.))
• ((Gastric cancer::A long-term complication, not the presenting finding.))
• ((Electrolyte imbalance::Not characteristic.))

Ménétrière disease — recognised long-term complication?

• ((Hyperacidity::Wrong direction.))
• ((Hypoalbuminaemia::A primary feature, not a complication.))
• ((B12 deficiency::Not the main long-term issue.))
• ((Electrolyte imbalance::Not characteristic.))
• ((Gastric adenocarcinoma::☑️ Hypertrophic gastropathies carry malignant potential.))

Delayed gastric emptying after gastrectomy — most likely contributor?

• ((Raised CCK::Slows emptying but not the primary surgical cause.))
• ((Vagotomy::☑️ Often performed with gastrectomy; loss of vagal drive impairs receptive relaxation and peristalsis.))
• ((Sympathetic loss::Would speed emptying, not slow it.))
• ((Raised secretin::Not the primary post-surgical mechanism.))
• ((Pyloric spasm::Pylorus is usually resected or bypassed.))

Post-bariatric: sweating, palpitations, convulsions. Diagnosis?

• ((Post-vagotomy gastroparesis::Causes bloating, not hypoglycaemia.))
• ((Insulinoma::Not specifically triggered by surgery.))
• ((Late dumping syndrome::☑️ Reactive hypoglycaemia 1–3 h after a meal — neuroglycopenic + adrenergic symptoms.))
• ((Addisonian crisis::Hypotension, hyperkalaemia, not post-prandial.))
• ((Carcinoid::Flushing, diarrhoea, wheeze.))

👩‍⚕️ Early dumping = osmotic (cramps, diarrhoea, hypotension within 30 min). Late dumping = reactive hypoglycaemia (sweating, tremor, confusion at 1–3 h).

Posterior gastric perforation — where does fluid collect first?

• ((Morison's pouch::In the greater sac — reached later, not first.))
• ((Greater sac::Anterior perforations drain here.))
• ((Lesser sac (omental bursa)::☑️ Sits directly behind the stomach — the immediate destination of posterior perforation.))
• ((Left paracolic gutter::Later spread, not first site.))
• ((Pelvis::Gravitational pooling later.))

👩‍⚕️ Lesser sac collections may be silent on initial imaging — a posterior perforation can lack the classic free subdiaphragmatic gas of an anterior perforation.

# Revision summary

- Cells: Parietal (HCl + IF, body), Chief (pepsinogen, body), G (gastrin, antrum), D (somatostatin), ECL (histamine).

- Three direct stimulators of parietal cell: ACh (M3, Ca²⁺), gastrin (CCKB, Ca²⁺), histamine (H2, cAMP — most direct). Final common pathway = H⁺/K⁺ ATPase.

- Three phases of acid secretion: cephalic (vagus, 30%), gastric (distension + gastrin, 60%), intestinal (initially +, then −, 10%).

- Master inhibitor: somatostatin from D cells (triggered by low pH). Duodenal inhibitors: secretin, CCK, GIP.

- Secretin = pancreatic bicarbonate. CCK = pancreatic enzymes + gallbladder contraction.

- PPIs irreversibly inhibit the proton pump. Cimetidine = P450 inhibitor + gynaecomastia.

- ZES: PPI-resistant ulcers, multiple/atypical sites, ↑↑ fasting gastrin, positive secretin stimulation, MEN1 in 25%.

- Pernicious anaemia: anti-parietal cell + anti-IF antibodies → B12 deficiency → macrocytic anaemia. Premalignant.

- Ménétrière: giant rugae, hypoalbuminaemia, hypoacidity, cancer risk.

- Dumping: early = osmotic; late = reactive hypoglycaemia.

- Gastric cancer signatures: Virchow's node, Krukenberg tumour, Sister Mary Joseph, signet ring/linitis plastica.

- Posterior perforation → lesser sac first. Anterior → greater sac.